CN109675041A - System, method and formulation for treating cancer - Google Patents

System, method and formulation for treating cancer Download PDF

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CN109675041A
CN109675041A CN201910036937.7A CN201910036937A CN109675041A CN 109675041 A CN109675041 A CN 109675041A CN 201910036937 A CN201910036937 A CN 201910036937A CN 109675041 A CN109675041 A CN 109675041A
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cancer
modification agent
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穆哈默德·M·D·尼扎米
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RESEARCH CANCER INSTITUTE OF AMERICA
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Abstract

This document describes the method and compositions for using at least two epigenetic modification agent treating cancers.In different implementation scenarios, it also uses hyperbaric oxygen ation and glycolysis inhibits therapy.

Description

System, method and formulation for treating cancer
Cross reference to related applications
This application claims enjoy in the entitled " targeting of immune dysfunction and cancer patient submitted on July 7th, 2011 Intravenous therapy " (TARGETED INTRAVENOUS THERAPIES FOR PATIENTS WITH IMMUNE DYSFUNCTION AND CANCER) No. 61/505,393 U.S. Provisional Application and in the name submitted on July 14th, 2011 Referred to as No. 61/507,950 U.S. Provisional Application of " method for the treatment of cancer " (METHOD FOR TREATING CANCER) Equity, herein all by reference be integrally incorporated.
Technical field
This disclosure relates to different systems, method for treating cancer patient (especially suffering from the patient of advanced cancer) And preparation.
Background of invention
2007, ten kinds of cancers being most often diagnosed included: prostate cancer, lung cancer, colon and rectum carcinoma in American male And bladder cancer；Cutaneous melanoma；Non Hodgkin lymphom；Kidney, oral cavity and throat cancer, leukaemia and cancer of pancreas.Women In, the most common cancer is reported as breast cancer, lung cancer and colon cancer.Generally speaking, there are 758,587 male's quilts in the U.S. in 2007 Them are informed with cancer, 292,853 males die of cancer.In women, National Cancer Institute (National Cancer Institute) monitoring in 2008, epidemiology and final result (Surveillance, Epidemiology, and End Results, SEER) there are the illness rates of 6,451,737 late cases for project report.In general, in prevention and control of diseases The heart (Centers for Disease Control and Prevention, CDC) the report U.S. in 2010 there are 11,957, 599 advanced cancers, and the incidence is almost unchanged between past 8 years that (482 in 2000,000 to 2008 456,000).Between 1999 to 2008, there is only about 0.6% variations every year for cancer incidence.Statistical data show by Death toll caused by all types of advanced cancers from before 10 years just not be improved significantly, and in some cases, such as lung Cancer, the death rate is rising, especially in women.Although being more introduced in market for the chemotherapeutics of terminal illness, Patient survival there is no change.In addition, the genotoxic potential of many chemotherapeutics may be all for clinician and patient It is monkey wrench.Therefore, the demand to the nontoxic therapy for being used alone or being applied in combination with conventional chemotherapy is apparent.
Summary of the invention
In various embodiments, it provides for preventing or the pharmaceutical preparation for the treatment of cancer, it includes two or more " epigenetic modification agent ".In other embodiments, epigenetic modification agent can for histone deacetylase inhibitor and/ Or demethylation agent.In other preferred embodiments, demethylation agent can be used as histone deacetylase inhibitor indirectly (HDACI), and vice versa.In other particularly preferred embodiments, epigenetic modification agent can be selected from: benzenebutanoic acid Sodium (SDB), lipoic acid (LA), Quercetin, valproic acid, hydralazine, Compound New Nomin (bactrim), green-tea extract (example Such as, Epigallo-catechin gallate (EGCG) (EGCG)), curcumin, sulforaphen and allicin/diallyl disulfide.? In preferred embodiment, a kind of epigenetic modification agent includes phenylbutyrate sodium (SPB), and another epigenetic modification agent packet Containing Quercetin.In another preferred embodiment of the present, a kind of epigenetic modification agent includes phenylbutyrate sodium (SPB), and another Epigenetic modification agent includes green-tea extract, such as Epigallo-catechin gallate (EGCG) (EGCG).
In other embodiments, pharmaceutical preparation can also include one or more glycolytic inhibitors.Further In embodiment, glycolytic inhibitor can be selected from: dichloroacetic acid, Octreotide and 2 deoxyglucoses (2DG).In other implementations In scheme, pharmaceutical preparation can also include one or more oxidants or antioxidant.In a further embodiment, it aoxidizes Agent or antioxidant are selected from: vitamin C, germanium, L-carnitine, taurine, glutathione, lysine, proline, hydrogen peroxide (H2O2) and dimethyl sulfoxide (DMSO).
In various embodiments, it provides for preventing or the pharmaceutical preparation of the unit dose for the treatment of cancer, it includes Two or more epigenetic modification agent of combining form, wherein the epigenetic modification agent is to be enough to cause in human body to swell The dosage of tumor response (for example, reduce tumor marker, reduce human tumour) exists, and the tumor response is giving about 1 unit dose It is measured after amount to about 60 unit doses by laboratory and/or radiologic investigation.In other different embodiments, use is provided In prevention or the pharmaceutical preparation of the unit dose for the treatment of cancer, it includes two or more epigenetic modifications of combining form Agent, wherein the epigenetic modification agent exists to be enough the dosage for causing immune system to enhance, the immune system enhancing is logical Cross human body white blood cell count(WBC) (WBC) and/or natural kill (NK) cell activity after giving about 1 unit dose to about 60 unit doses Increase measure.
In other embodiments, kit is provided comprising for preventing or the medicine of the unit dose for the treatment of cancer Object preparation and container, the pharmaceutical preparation include two or more epigenetic modification agent, and the unit dose is at least partly It is included in the container.
In various embodiments, the method for prevention or treatment is provided comprising give treatment of animals a effective amount of two Kind or a variety of epigenetic modification agent.In one embodiment, prevent or treat to be for cancer.In preferred embodiments, Cancer is the cancer of epigenetic driving.In another particularly preferred embodiment, cancer is selected from: glioma, colon cancer, pancreas Gland cancer, leukaemia, non-small cell lung cancer and chromoma.In another preferred embodiment of the present, cancer is anoxic.
In another embodiment, the method for prevention or treatment is provided comprising it is external or internal to give animal model One or more epigenetic modification agent of cancerous cell line or culture therapeutic dose, and animal is made to be subjected to high pressure oxygen environment.One In specific embodiment, one or more epigenetic modification agent can be given before making animal be subjected to hyperbaric oxygen.Optional In specific embodiment, one or more epigenetic modification agent can be given after making animal be subjected to hyperbaric oxygen.It is another can It, can be making animal give one or more epigenetics before and after being subjected to high pressure oxygen environment in the specific embodiment of choosing Dressing agent.In another embodiment, epigenetic modification agent can be given alone or in combination.In particularly preferred reality It applies in scheme, so that animal is subjected to high pressure oxygen environment and occur about 24 before or after giving one or more epigenetic modification agent In hour.In the second preferred embodiment, so that animal is subjected to high pressure oxygen environment and occur to repair giving one or more epigenetics About 5 minutes to about 90 minutes before or after decorations agent.In third preferred embodiment, animal is made to be subjected to the generation of high pressure oxygen environment About 30 minutes to about 3 hours before or after giving one or more epigenetic modification agent.
In another embodiment, for any preceding method, chemotherapy or radiation can be one or more additional steps Suddenly, occur before or after giving any epigenetic modification agent, either in the form of alone or in combination, separated or mixed Close, before or after making animal be subjected to high pressure oxygen environment.
In various embodiments, the method for prevention or treatment is provided comprising it is external or internal to give animal model The one or more glycolytic inhibitors or dressing agent of cancerous cell line or culture therapeutically effective amount, and animal is made to be subjected to hyperbaric oxygen Environment.In a particular embodiment, make animal be subjected to high pressure oxygen environment occur give one or more glycolytic inhibitors or Before or after dressing agent in about 24 hours.In the second preferred embodiment, so that animal is subjected to the generation of high pressure oxygen environment and giving About 5 minutes to about 90 minutes before or after one or more glycolytic inhibitors or dressing agent.In another particularly preferred reality Apply in scheme, make animal be subjected to high pressure oxygen environment occur before giving one or more glycolytic inhibitors or dressing agent or it About 30 minutes to about 3 hours afterwards.
In other embodiments, the method prevented or treated include give external animal model or internal cancerous cell line or The one or more glycolytic inhibitors or dressing agent of culture therapeutically effective amount, and give treatment of animals it is a effective amount of a kind of or A variety of epigenetic modification agent.In a particular embodiment, one or more glycolytic inhibitors are given and one or more tables It sees genetic modification agent and gives and occur before or after each other in about 24 hours.It is a kind of or more in the second specific embodiment Kind of glycolytic inhibitor give generation before or after giving one or more epigenetic modification agent and giving about 5 minutes to about 90 minutes.In third specific embodiment, one or more glycolytic inhibitors give generation in one or more apparent something lost It passes after dressing agent is given about 30 minutes to about 3 hours.
In one embodiment, it provides for preventing or the pharmaceutical preparation for the treatment of cancer, it includes two kinds or more Kind epigenetic modification agent.
In a particular embodiment, described two or a variety of epigenetic modification agent be histone deacetylase inhibitor or Demethylation agent.
In a particular embodiment, described two or a variety of epigenetic modification agent are selected from: phenylbutyrate sodium (SPB), sulphur are pungent Sour (LA), Quercetin, valproic acid, hydralazine, Compound New Nomin, green-tea extract, Epigallo-catechin gallate (EGCG), Curcumin, sulforaphen and allicin/diallyl disulfide.
In a particular embodiment, the pharmaceutical preparation includes phenylbutyrate sodium (SPB) and Quercetin.
In a particular embodiment, the pharmaceutical preparation is to include about 1.0g to about 10.0g phenylbutyrate sodium (SPB) peace treaty 0.5g to about 1.5g Quercetin unit dose.
In a particular embodiment, the pharmaceutical preparation includes Quercetin and lipoic acid (LA).
In a particular embodiment, the pharmaceutical preparation is comprising about 0.5g to about 1.5g Quercetin and about 200mg to about The unit dose of 1000mg lipoic acid (LA).
In a particular embodiment, the pharmaceutical preparation includes lipoic acid (LA) and phenylbutyrate sodium (SPB).
In a particular embodiment, the pharmaceutical preparation is to include about 200mg to about 1000mg lipoic acid (LA) peace treaty 1.0g to about 10.0g phenylbutyrate sodium (SPB) unit dose.
In a particular embodiment, the pharmaceutical preparation includes green-tea extract and phenylbutyrate sodium (SPB).
In a particular embodiment, the pharmaceutical preparation is to include about 100mg to about 1.5g green-tea extract and about 1.0g To the unit dose of about 10.0g phenylbutyrate sodium (SPB).
In a particular embodiment, the pharmaceutical preparation also includes one or more oxidants or antioxidant.
In a particular embodiment, one or more oxidants or antioxidant are selected from: vitamin C, germanium, left-handed meat Alkali, taurine, glutathione, lysine, proline, hydrogen peroxide (H2O2) and dimethyl sulfoxide (DMSO).
In a particular embodiment, the pharmaceutical preparation also includes one or more pharmaceutically acceptable excipient, dilution Agent or carrier.
In a particular embodiment, the pharmaceutical preparation also includes at least one of physiological saline and D5 salt water.
In a particular embodiment, the pharmaceutical preparation is suitable for intravenous administration to human body.
In a particular embodiment, the pharmaceutical preparation also includes one or more glycolytic inhibitors.
In a particular embodiment, one or more glycolytic inhibitors are selected from: dichloroacetic acid, Octreotide and 2 are de- Oxygen glucose (2DG).
In another embodiment, the pharmaceutical preparation of the unit dose for treating cancer is provided, it includes two Kind or polymorphic epigenetic modification agent, wherein the epigenetic modification agent is to be enough to cause tumour to be answered in human body The dosage answered exists, and the tumor response passes through laboratory and/or radiation after giving about 1 unit dose to about 60 unit doses Research is learned to measure.
In another specific embodiment, the pharmaceutical preparation of the unit dose for treating cancer is provided, it includes two Kind or polymorphic epigenetic modification agent, wherein the epigenetic modification agent is to be enough that immune system is caused to enhance Dosage exist, immune system enhancing is by giving human body white blood cell count(WBC) after about 1 unit dose to about 60 unit doses (WBC) and/or the increase of natural kill (NK) cell activity measures.
In one embodiment, kit is provided comprising: the drug system of the unit dose for treating cancer Agent, it includes two or more epigenetic modification agent；Container, the unit dose are at least partly contained therein.
In a particular embodiment, described two or a variety of epigenetic modification agent include that demethylation agent or histone are de- Acetyl enzyme inhibitor (HDACI).
In a particular embodiment, the epigenetic modification agent is selected from: phenylbutyrate sodium (SDB), lipoic acid (LA), quercitrin Element, valproic acid, hydralazine, Compound New Nomin, green-tea extract, curcumin, sulforaphen and allicin/diallyl disulfide Object.
In a particular embodiment, the kit further include the first sub- container containing the first epigenetic modification agent and The second sub- container containing the second epigenetic modification agent.
In a particular embodiment, the kit further includes the first epigenetic modification agent containing combining form and The sub- container of two epigenetic modification agent.
In a particular embodiment, the kit further includes for instructing the memory for giving the unit dose to assist Object.
In another embodiment, treatment method is provided comprising: it is one or more apparent to give mammal Genetic modification agent；And the mammal is made to be subjected to high pressure oxygen environment.
In a particular embodiment, the high pressure oxygen environment in method comprises more than about 95% O2Atmosphere.
In a particular embodiment, described in method is subjected to occurring to give in about 24 hours described.
In a particular embodiment, described in method is subjected to occurring before or after described give about 5 minutes to about 90 minutes.
In a particular embodiment, described in method is subjected to occurring before or after described give about 30 minutes to about 3 hours.
In a particular embodiment, one or more epigenetic modification agent in method include one or more de- Methylating agent or histone deacetylase inhibitor (HDACI).
In a particular embodiment, one or more epigenetic modification agent in method are selected from: phenylbutyrate sodium (SPB), lipoic acid (LA), Quercetin, valproic acid, hydralazine, Compound New Nomin, green-tea extract, curcumin, sulforaphen With allicin/diallyl disulfide.
In a particular embodiment, one or more epigenetic modification agent in method include phenylbutyrate sodium (SPB)。
In a particular embodiment, one or more epigenetic modification agent in method include lipoic acid (LA).
In a particular embodiment, one or more epigenetic modification agent in method include Quercetin.
In a particular embodiment, one or more epigenetic modification agent in method include Quercetin and benzene fourth Sour sodium (SPB).
In a particular embodiment, described give in method includes: with about 0.5g in physiological saline to the agent of about 1.5g Amount gives Quercetin through vein；Phenylbutyrate sodium is given through vein with the dosage of about 1.0g to about 10.0g in physiological saline (SPB)。
In a particular embodiment, one or more epigenetic modification agent in method include that Quercetin and sulphur are pungent Sour (LA).
In a particular embodiment, described give in method includes: with about 0.5g in physiological saline to the agent of about 1.5g Amount gives Quercetin through vein；Lipoic acid (LA) is given through vein with the dosage of about 200mg in physiological saline to about 1000mg.
In a particular embodiment, one or more epigenetic modification agent in method include lipoic acid (LA) and Phenylbutyrate sodium (SPB).
In a particular embodiment, described give in method includes: with about 200mg in physiological saline to about 1000mg Dosage gives lipoic acid (LA) through vein；Benzenebutanoic acid is given through vein with the dosage of about 1.0g to about 10.0g in physiological saline Sodium (SPB).
In a particular embodiment, the epigenetic modification agent in method includes green-tea extract and phenylbutyrate sodium (SPB)。
In a particular embodiment, described give in method includes: with about 100mg in physiological saline to the agent of about 1.5g Amount gives green-tea extract through vein；Phenylbutyrate sodium is given through vein with the dosage of about 1.0g to about 10.0g in physiological saline.
In a particular embodiment, method is further comprising administering to the one or more glycolytic inhibitors of mammal.
In a particular embodiment, method is further comprising administering to the one or more oxidants of mammal or antioxidant.
In another specific embodiment, treatment method is provided comprising: give mammal one or more sugared ferment Solve inhibitor；And the mammal is made to be subjected to high pressure oxygen environment.
In a particular embodiment, the high pressure oxygen environment in method comprises more than 95% O2Atmosphere.
In a particular embodiment, described in method is subjected to occurring to give in about 24 hours described.
In a particular embodiment, described in method is subjected to occurring before or after described give about 5 minutes to about 90 minutes.
In a particular embodiment, described in method is subjected to occurring 30 minutes to about 3 before or after described give Hour.
In a particular embodiment, one or more glycolytic inhibitors in method include dichloroacetic acid, song difficult to understand At least one of peptide and 2 deoxyglucoses (2DG).
In a particular embodiment, method is further comprising administering to the one or more HDACI of patient.
In a particular embodiment, method is further comprising administering to the one or more oxidants of patient or antioxidant.
In an also specific embodiment, treatment method is provided comprising: give mammal one or more sugared ferment Solve inhibitor；With give mammal one or more epigenetic modification agent.
In a particular embodiment, one or more glycolytic inhibitors in method include dichloroacetic acid, song difficult to understand At least one of peptide and 2 deoxyglucoses (2DG).
In a particular embodiment, one or more epigenetic modification agent in method include demethylation agent or Histone deacetylase inhibitor (HDACI).
In a particular embodiment, one or more epigenetic modification agent in method are selected from: phenylbutyrate sodium (SDB), lipoic acid (LA), Quercetin, valproic acid, hydralazine, Compound New Nomin, green-tea extract, epigallocatechin Gallate, curcumin, sulforaphen and allicin/diallyl disulfide.
In a particular embodiment, method is further comprising administering to the one or more oxidants of patient or antioxidant.
Detailed description of the invention
Following description, embodiment and data provide the complete description of preparation and application the compounds of this invention.Due to can Many embodiments of the invention are formed not depart from the spirit and scope of the present invention, the invention belongs to hereafter appended rights to want It asks.There is provided examples detailed above is to provide and how to prepare and using the preferred of the composition and method to those skilled in the art The complete disclosure and explanation of embodiment, and it is not intended to limit the range that the present inventor is considered its summary of the invention. The modification for the above-mentioned mode of the implementation present invention that will be apparent to those skilled in the art is considered the range in following the claims It is interior.Unless expressly stated, application is defined below.
Definition
Term " giving (administer/administration) ", " delivering (deliver/ as used herein Delivery) " refer to via tablet, capsule, soft capsule, intravenous, intramuscular, and/or subcutaneous injection, transdermal patch, creme, coagulate Glue or other mechanism known in the art or hereafter develop give body.
Term " active constituent " as used herein can refer to there is or be expected biologically active any substance.
Term " combining form " as used herein can refer to that two or more active constituents are present in same medium.Example Such as, if active components A and active constituent B be all present in same salt it is water-borne in, it may be considered that active components A and activity at The mixture for dividing B is combining form.
Term " epigenetic modification agent " as used herein can refer to influence, be considered influencing or tend to influence gene The substance of expression and function.Same as used herein " epigenetic driving " can refer to influenced by expression and function of genes or Tend to any substance influenced by expression and function of genes.
Term " glycolytic inhibitor " as used herein can refer to inhibition, be considered inhibiting or tend to inhibit cancer cell The substance of the glycolysis of middle appearance.
Term " salt water " as used herein can refer to sterile or substantially sterile sodium-chloride water solution.Salt water can fit Together in intravenous administration to human body.
Term " unit dose " as used herein can refer to the amount or volume for attempting once to give the pharmaceutical preparation of patient.
Description
It has been found that application of two or more epigenetic modification agent in treating cancer can produce unexpected collaboration Therapeutic effect.Specifically, it gives altogether, preparation and/or temporarily intensive giving tend to produce particularly effective result altogether.This Outside, in various embodiments, therapeutic effect also can be improved in hyperbaric oxygentherapy.It has also been found that in addition to two or more epigenetics are repaired Agent is adornd, different antioxidant and glycolytic inhibitor can also be advantageously used.It is any epigenetic modification agent, anti-oxidant Agent, the giving altogether of glycolytic inhibitor and/or hyperbaric oxygentherapy are prepared and/or interim intensive give can be with any suitable altogether Sequence occur, but can before or after each other in about 24 hours, each other before or after about 5 minutes to about 90 minutes, or Occur within about 30 minutes to about 3 hours before or after each other.
According to different embodiments, preparation includes two or more epigenetic modification agent.Epigenetic modification agent can Change the genetic expression in cancer cell and precancerous cell to work together.Epigenetic modification agent be can choose increasing or Reduce genetic expression.For example, epigenetic modification agent can be used to reduce rat sarcoma (" Ras ") family gene and/or b- The expression of cell lymphoma 2 (" bcl-2 ") gene.
The epigenetic modification agent occurred in different embodiments includes but is not limited to, histone deacetylase inhibitor and Demethylation agent.Demethylation agent be by inhibit or tend to inhibit methylase and inhibit or tend to inhibit DNA and/or Histone methylated reagent, such as dnmt rna (DNMT) or histone methyltransferase.Demethylation chemotherapeutics includes But it is not limited to, cytidine analog, such as 5-azacitidine (azacitidine) and 5- aza deoxycytidine (Decitabine).Especially, Known HDACIs may interfere with or tend to interfere with histone deacetylase.Histone deacetylase is can to remove acetyl from histone The enzyme of base, and be active before transcription.In addition to other features, also show that some epigenetic modification agent also can inhibit Angiogenesis.
In various embodiments, although the present invention is contemplated that, using any epigenetic modification agent, HDACIs may be Indirectly (for example, being worked by indirect mode, change directly (for example, by working with target enzyme direct correlation) or such as Chromatin shape).In addition, HDACI may include one of following or a variety of: phenylbutyrate sodium (" SPB "), lipoic acid (" LA "), Quercetin, valproic acid, hydralazine, Compound New Nomin, green-tea extract are (for example, Epigallo-catechin gallate (EGCG) (EGCG)), curcumin, sulforaphen and allicin/diallyl disulfide.
SPB is classified as the rare medicine for being used to treat urea cycle dysbolism by FDA at present.Before benzenebutanoic acid salt (" PB ") is Medicine.In human body, PB is that phenylacetate is metabolized by beta oxidation.Phenylacetate and glutamine are conjugated to form phenylacetyl paddy Glutamine is finally drained in urine.Benzenebutanoic acid (" PBA ") have in model system in vitro and in vivo growth inhibition and point Change induced activity.Although not fettered by the theory, it is believed that PBA can make the cell cycle stop at its G1-G0 phase.PB is efficient HDACI, and be considered to induce cell apoptosis by c-jun N terminal kinase (" JNK ").In lung carcinoma cell, 56p21wafl, tumor necrosis factor (TNF)-α 58 or the peroxisome proliferation of growth retardation are mediated in MCF-7 cell Activated receptor (PPAR) λ mediate cell differentiation, and it is more more effective than phenylacetate in prostate gland cancer cell, while increasing MHC The expression of I class.PB by being converted into active metabolite phenylacetate (" PA ") in liver and the Intramitochondrial beta oxidation of kidney in vivo.It is more Number dose limit poisoning is tired, nauseous and drowsiness.The patient with recurrent glioblastoma multiforme is carried out Primary Study.Think that SPB plays work more than 100 kinds of genes by influencing NF κ-B access, reducing inflammatory reaction and lower With.
The toxicity research of SPB shows that up to 36 grams daily of oral dose shows minimum toxicity.In a research, 25% patient when taking drugs stable disease more than 6 months.The SPB tolerance of oral form is good, and has reached in body Show biologically active bulk concentration outside.It works it has been shown that SPB can be used as cytostatics.However, in majority In research, SPB is orally used using rather than through vein.
In various embodiments, Quercetin is used as HDACI.Quercetin is also act as cancer stem cell differentiation agent, perhaps The blocking agent of multi-path and signaling molecule, chemotherapeutic sensitizer and apoptosis agent.Quercetin is the polyphenyl extracted from apple.? Propose several mechanism of display Quercetin anticarcinogenic effect.Have shown Quercetin can with various kinds of cell acceptor interaction, and Quercetin inhibit G1 the and G2 phase cell growth, inhibit tyrosine kinase to prevent uncontrolled proliferation, influence estrogen by Body, and interact with heat shock protein to prevent to be proliferated.
Also show that Quercetin can interact with receptor as participated in the Raf and MEK of tumor proliferation.Also suspect presence and its The interaction of his receptor such as cell surface receptor.Additionally, it is believed that Quercetin may be used as the dressing agent of signal transduction.According to report Road, Quercetin influence the source that Cycle Regulation, cell death, inflammatory reaction and new blood supply are answered.
Toxicity research has been carried out to Quercetin.Quercetin open label, the examination of non-controlling Dosage clinic are carried out It tests.In this experiment, the up to Quercetin of 1700mg/m2 increment value through vein gives 50 patients about 3 weeks, these patients suffer from The cancer that can not be treated is thought by conventional method.Various cancer patients, including colorectal cancer, gastric cancer, cancer of pancreas, ovary are treated Cancer and melanoma.There is no patient to reach the inhibition defined by the radiology standard of WHO, but two patients are after Quercetin therapy Show peculiar cancer markers lasting reduction (one suffer from metastatic hepatocellular carcinoma, another name suffer from 4 phase Metastatic carcinoma in the ovary And reactionless to chemotherapy before).In addition, measuring 11 individual tyrosine-kinase enzyme levels, and it is reported in 9 individuals and drops It is low.Tyrosine kinase is usually studied in oncology, because it can cause cancer by the signal of covering control cell growth Uncontrolled proliferation.Therefore, infer that Quercetin there may be the ability for inhibiting tyrosine kinase, and should be not higher than It is furtherd investigate under the dosage of 1400mg/m2.Several in vitro tests supported the research as a result, wherein Quercetin draws Play the inhibition of tyrosine-kinase expression of enzymes in pernicious and non-malignant cell.
Although not fettered by the theory, since its genetic regulation acts on, including for example, RAS gene and bcl-2 gene are reduced Genetic expression, thus it is speculated that Quercetin can all show promising effect in the almost treatment of every kind of cancer cell.Also show Mongolian oak Pi Su has prevention effect in cancer generation.In current smoker, Quercetin intake and cancer of pancreas are negatively correlated, it is shown that Relative risk between the highest and lowest quintile of intake substantially reduces (0.55).
Other epigenetic therapies are combined to grind through vein using the human body of its effect when Quercetin however, not appearing to concern Study carefully.
In various embodiments, lipoic acid (" LA ") is used as HDACI.Lipoic acid is also a kind of for glycolysis therapy Topoisomerase enzyme inhibitor and oxidant.In low-level, LA is the co-factor of pyruvic dehydrogenase in mitochondria.Human body is not LA is synthesized, and enough amounts cannot be obtained in diet or food.Naturally occurring LA is not directly available from dietary source. Low-level LA is related to various disease states.LA is generally considered to be safe and nontoxic.
Recently, it is believed that the main effects of LA is the inducer as response to oxidative stress.In view of this point, hyperbaric oxygen is used Treatment, LA may be effectively to the oxidation in the combination treatment of cancer by booster injection.Have shown alpha-lipoic acid by increasing line grain Body respiration simultaneously generates along with oxygen radical and induces apoptosis of human colon cancer cells.Several researchs provide alpha lipoic acid can Effectively to induce the proof of apoptosis of human colon cancer cells by enzymatic oxidation mechanism, the enzymatic oxidation mechanism is by increasing oxidable bottom Object is absorbed into mitochondria and initiates.
Nearest researches show that the prospects treated in following a variety of Murine cancer models cancer cells using LA: MBT-2 wing Guang transitional cell carcinoma, B16-F10 melanoma and LL/2Lewis lung cancer.Think that LA reduces cancer cell survival ability and increases cell DNA fragmentation.In general, it by inducing cell apoptosis the anticancer effect for seeming that LA can be mediated, induces cell apoptosis and passes through It is completed by the access for not depending on caspase and relying on caspase that intracellular Ca2+ is mediated.LA is typically considered peace It is complete and nontoxic.Alpha-lipoic acid is licensed as treatment polyneuropathy in Germany, as diabetic keratopathy and Alcoholic are multiple The drug of neuropathy and hepatopathy.
Green-tea extract, such as Epigallo-catechin gallate (EGCG) (EGCG), also referred to as epigallocatechin 3- does not have Infanticide acid esters, is also considered for the present invention.EGCG is the ester of epigallocatechin and gallic acid, is one kind of catechin Type.EGCG is the most abundant catechin in tea, and is effective antioxidant, is treating many illnesss (such as cancer) In have treatment use.It usually exists in green tea rather than in black tea；Black tea manufacture during, catechin be converted into theaflavin and Thearubigin.EGCG is present in many replenishers.
More and more evidences show that EGCG can be beneficial to treat certain cancers together with other flavonoids, including the cancer of the brain, preceding Column gland cancer, cervical carcinoma and bladder cancer.Have shown that EGCG combines and inhibit Anti-apoptotic proteins Bcl-xl, which is related to cancer The survival of cell and normal cell.Similarly, EGCG is found, it to be majorant topology isomerase inhibitors that there are also other tea polyphenols, similar In some chemotherapeutic anti-cancer disease drugs, such as Etoposide and adriamycin.
According to different embodiments, the preparation comprising one or more HDACIs can be combining form.
According to different embodiments, preparation, system and method can also include one or more pharmaceutically acceptable figurations Agent.Preparation can individually give or with other one or more compound combinations disclosed herein or with it is one or more other Pharmaceutical composition (or as any combination thereof) is given.In general, preparation described herein is as can with one or more pharmacy The preparation of the excipient composition of receiving is given.The selection of excipient largely depends on the ad hoc fashion such as given, assigns Influence and dosage form qualitative factor of the shape agent to dissolubility and stability.
The pharmaceutical composition and their preparation method for being suitble to delivering the compounds of this invention are aobvious to those skilled in the art And it is clear to.Such composition and their preparation method can be for example, " Lei Shi pharmacy is complete works of " (Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, 1995) it finds, leads in Reference is crossed to be integrally incorporated herein.
According to different embodiments, preparation may include any pharmaceutically acceptable carrier or diluent, such as salt water.Physiology Salt water may include sterile water and sodium chloride.It is, for example, possible to use physiological saline and/or D5 salt water.D5 salt water includes to have 5% The salt water of glucose.
Preparation of the invention can also be directly administered to blood flow, muscle or internal.The appropriate parties that parenteral is given Formula includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, in breastbone, encephalic, intramuscular and subcutaneous administration.Intestines The appropriate device given outside stomach includes needle (including micropin) syringe, needleless injector and infusion techniques.
Parenteral administration is usually aqueous solution, can contain excipient, such as salt, carbohydrate and buffer (preferably from about pH 3 To about pH 11), for some applications, however, it may be more suitable for for they being made sterile anhydrous solution or together with it is such as sterile, The dried forms that the suitable carrier of no heat source water uses.
The preparation of parenteral administration under aseptic condition, for example, can easily use art technology by freeze-drying Standard pharmaceutical techniques known to personnel are completed.
The pharmaceutically acceptable salt that compound is disclosed herein includes its acid-addition salts and alkali salt.Suitable acid-addition salts are by shape It is formed at the acid of nontoxic salts.Example includes but is not limited to: acetate, aspartate, benzoate, benzene sulfonate, bicarbonate Salt/carbonate, bisulphate/sulfate, borate, camsilate, citrate, ethanedisulphonate, esilate, formic acid Salt, fumarate, gluceptate, gluconate, glucuronate salt, hexafluorophosphate, hibenzate (hibenzate), hydrochloride/chloride, hydrobromate/bromide, hydriodate/iodide, isethionate, lactic acid Salt, malate, maleate, malonate, mesylate, metilsulfate, naphthoate (naphthylate), 2- naphthalene sulfonic acids Salt, nicotinate, nitrate, Orotate, oxalates, palmitate, embonate, phosphate/phosphor acid hydrogen salt/biphosphate Salt, sugar lime, stearate, succinate, tartrate, toluene fulfonate and trifluoroacetate.
Suitable alkali salt is formed by the alkali of formation nontoxic salts.Example includes: aluminium salt, arginine salt, tardocillin salt (benzathine), calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycinate, lysine salt, magnesium salts, meglumine salt, Ethanolamine salt, sylvite, sodium salt, amino butanetriol salt (Tromethamine) and zinc salt.
Half salt (hemisalts) of bronsted lowry acids and bases bronsted lowry can also be formed, for example, Hemisulphate and half calcium salt.
By one of following three kinds of methods or a variety of it can prepare the pharmaceutically acceptable of active constituent disclosed herein Salt (although any method for preparing pharmaceutically acceptable salt can be used):
(i) compound of active constituent disclosed herein is reacted with desired acid or alkali；
(ii) using desired acid or alkali, sour unstable or alkali is sloughed not from the appropriate precursors of active constituent disclosed herein Stablize protecting group, or will suitable annular precursor such as lactone or lactams open loop；Or
(iii) by a kind of salt of active constituent disclosed herein by with it is suitable acid or alkali react or pass through suitably from Sub- exchange column method is converted into another salt.
All three reactions usually all carry out in the solution.The salt of generation can be collected by filtering precipitating, or can be with By evaporating solvent recovery.The degree of ionization of the salt of generation can change in complete ionization between almost unionization.It is right In the summary of suitable salt, referring to " pharmaceutical salts handbook: property, selection and application " (Handbook of of Stahl and Wermuth Pharmaceutical Salts:Properties,Selection,and Use,Wiley-VCH,Weinheim,Germany, 2002), wherein all applicable parts are all incorporated herein by reference.
In various embodiments, two or more active constituents may not be combination shape such as two or more HDACIs Formula, but can be given altogether.Giving altogether may include while or giving patient within the intensive period.It can for example, giving altogether To include giving SPB and Quercetin simultaneously.Further for example, giving altogether may include being spaced each other about 24 hours in, or each other Between be spaced about 1 minute to about 60 minutes, or be spaced to each other about 5 minutes to about 90 minutes, or be spaced to each other about 30 minutes SPB and Quercetin were given to about 3 hours.
In various embodiments, may exist one or more oxidants or antioxidant.Example includes but is not limited to: Vitamin C, germanium, L-carnitine, taurine, glutathione, lysine, proline, hydrogen peroxide (H2O2) and dimethyl sulfoxide (DMSO).Oxidant can be any chemicals, substance, molecule or the compound of release or auxiliary release free radical, described Free radical causes to destroy cell, including cancer cell.In general, oxidant (oxidizing agent/oxidizer/ Oxidiser) electronics is sloughed from another reactant in redox chemistry reaction.Oxidant obtains electronics by its own And by " reduction ", and reactant is seized by its electronics by " oxidation ".Antioxidant can be delay or prevention substrate oxygen Any chemicals, substance, molecule or the compound changed.In general, antioxidant reduces oxidizing reaction rate, the oxidation Reaction is to be related to for electronics being transferred to the chemical reaction of oxidant from a kind of substance.Antioxidant can by with intermediate reaction And directly stop oxidation reaction, or by with oxidant reaction and oxidation reaction is prevented to react to slow down these.It is same Substance different environment or under the conditions of may be used as oxidant or antioxidant.Specifically, the dosage of substance can determine Substance is used as oxidant or antioxidant.For example, the vitamin C of 25 grams of IV dosage has oxidation or oxidant property, but In lower dosage, vitamin C has anti-oxidant properties.
In various embodiments, may exist one or more glycolytic inhibitors.Example includes but is not limited to: dichloro Acetic acid, Octreotide and 2 deoxyglucoses (2DG).However it has been found that and not all glycolytic inhibitor is all effective.Specifically For, although previous 3 bromacetone hydrochlorate of research and utilization (as glycolysis alkylating agent and inhibitor) carrys out target cancer cell, It is not found in the present invention effectively or is used.In general, about glycolytic inhibitor, the plan of a kind of destruction or pre- anti-cancer The cellular energy for slightly targeting them generates point.There is the people's cell of core that there are two class source generating units, i.e., it is " high by ADP manufacture The system of energy " compound ATP.One kind is " glycolysis ", and another kind of is " mitochondria ".Mitochondria is main in non-cancerous cells ATP producer (> 90%).However, human cancer tends to rely on both mechanism.Glycolysis can contribute the ATP close to half, (referred to as " Warburg effect ") even in the presence of oxygen.Therefore, glycolytic inhibitor may be in the treatment of various cancers Useful.
Dichloroacetic acid (" DCA ") is the by-product of water chlorination.By stimulating the activity of pyruvate dehydrogenase, DCA promotes Lactate aoxidizes and reduces acquired and lactic acidosis,congenital disease incidence.Dichloroacetic acid salt ion is by inhibiting enzyme (third Ketonic acid salt dehydrogenase kinase) and stimulate the activity of enzyme (pyruvate dehydrogenase).Therefore, by being metabolized acetonate from sugar Glycolysis turns to mitochondrial oxidative and reduces lactate generation.
Cancer cell, which tends to be metabolized the method in a manner of oxygen to change it, promotes their survival.Solid tumor, including invasion Property primary brain cancer glioblastoma multiforme, develops the resistance to cell death, is partly due to from mitochondrial oxidation Phosphorylation is converted to cytoplasm glycolysis.In vitro and in vivo, DCA makes mitochondrial depolarization, increases mitochondria reactive oxygen Class, and induce the cancer cell-apoptosis of glycolysis.
In vivo and in vitro, DCA therapy also inhibits hypoxia-inducible factor-1 alpha, promotes p53 activation and inhibits angiogenesis. There are the Preclinical evidences that a large amount of DCA may be beneficial to human cancer in vitro and in vivo model.In addition, passing through DCA activation of wire grain Body and increase the O in tumour2Consumption, and greatly in enhancing animal model the effect of anoxic specific chemotherapies.In tissue cultures In the laboratory research of isolated growth of cancer cells, DCA restores original metabolism, and promotes their self-destructions.
Octreotide (trade (brand) name) it is pharmacologically to simulate the eight of natural growth hormone inhibin Peptide, but natural hormone is compared, it is growth hormone, glucagon and the more effective inhibitor of insulin.Octreotide is in skin It is quickly and completely absorbed after lower application.Reach maximal plasma concentration after 30 minutes.
Oncogene can express " tyrosine kinase receptor access " albumen, the albumen be include that insulin or IGF- growth swash The receptor family of plain receptor.Other oncogenes change the PP2A phosphatase for hindering these kinases.From 1979, Octreotide was used In plurality of medical illness.Since it inhibits insulin secretion, the inhibitor of insulin-like growth factor 1 (IgF1) is also served as, has been mentioned View is used for the cancer of a variety of glycolysis.As indicated in through zoopery, it has been found that Octreotide has to benefits subjects' Treatment use.
The synthesis and release of GH hormone induced insulin like growth factor (IGF) in liver.The latter activation such as pancreas islet Element --- IGF- tyrosine kinase receptor (IGFR) causes map kinase-ERK mitogenesis signal.Under normal physiological, GH The triglyceride fats enzyme in fat cell is stimulated, fatty acid release and its beta-oxidation are increased.Concurrently, GH can close acetyl The glycolysis source of CoA may inhibit hexokinase and mitochondria to interact.Make it possible that this effect of Apoptosis exists Do not occur but in tumour cell.
Due to may expect to give the composition of active constituent, for example, in order to treat the purpose of specified disease or illness, two The kit form that kind or a variety of pharmaceutical preparations may adapt to give composition altogether easily combines also in the scope of the present disclosure It is interior.
Therefore, kit disclosed herein includes two or more individual pharmaceutical preparations and individually saves the preparation Tool, wherein at least one of described pharmaceutical preparation contain active constituent described herein, the tool such as container, separate Bottle or the Foilpac separated.One example of such kit is the common blister package for package troche, capsule etc..
Kit is particularly suitable for giving different dosage forms, such as oral and parenteral, for different spacing of doses Individual composition is given, or for being directed to individual composition titrating to each other.In order to facilitate compliance, kit is usually wrapped It includes and is described book, and can be provided together with memory aids.
The compounds of this invention can exist in the form of solvate and non-solvate.Term " solvate " is herein For describing point of one or more pharmaceutically acceptable solvent molecule such as ethyl alcohol comprising the compounds of this invention and stoichiometry Sub- compound.Term " hydrate " is used when the solvent is water.
The compound being included within the scope of the invention such as clathrate complex, drug-host inclusion complex, wherein phase Than previously mentioned solvate, drug and main body exist with stoichiometry or non-stoichiometry.It further include containing there are two types of or more Organic and/or inorganic component the pharmaceutical complex of kind can exist with stoichiometry or non-stoichiometry.The compound of generation can It is thinking ionization, partial ionization or unionization.For such compound summary referring to Haleblian (1975 Year August) J Pharm Sci, 64 (8), 1269-1288 is incorporated herein by reference in their entirety.
Hereafter it is all refer to active constituent as disclosed herein include refer to salt, solvate and its compound and its The solvate and compound of salt.
Active constituent disclosed herein include all polymorphs defined below for active constituent disclosed herein and its Crystal habit, prodrug and its isomers (including optics, geometry and tautomer).For example, all HDACIs disclosed herein It include all polymorph and its crystal habit, prodrug and its isomers (including optics, geometry and mutually with glycolytic inhibitor Tautomeric).
As pointed, the active constituent disclosed herein for being known as " prodrug " is also within the scope of the invention.Therefore originally Certain derivatives of active constituent disclosed in text, it is possible itself to there is little or no pharmacological activity, when being administered to body When on interior or body, the derivative can be converted into it is disclosed herein have it is expected active active constituent, for example, passing through water Solution cracking.This analog derivative is referred to as " prodrug ".It can be found in the following documents using the other information of prodrug: Prodrugs as Novel Delivery Systems,Vol.14,ACS Symposium Series(T.Higuchi and W.Stella) With Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed.E.B.Roche, American Pharmaceutical Association), it is incorporated herein by reference in their entirety.
For example, according to the disclosure, it can be by using certain parts well known by persons skilled in the art as " preceding part " The appropriate functional group being present in active constituent disclosed herein is replaced to generate prodrug, " the preceding part " is described in, for example, " prodrug design " (the Design of Prodrugs) of H.Bundgaard (Elsevier, 1985) is integrally incorporated by reference Herein.
According to previous embodiment, the reference that the example of substituent group and the example of other prodrug types can refer in front is literary It is found in offering.
The scope of the present invention further includes the metabolin of active constituent disclosed herein, i.e., is formed in vivo by giving drug Compound.
The compound of active constituent disclosed herein can contain one or more asymmetric carbon atoms, can be used as two kinds Or multiple stereoisomers exist.When active constituent disclosed herein contains alkenyl or alkenylene (alkenylene), Ke Nengyou Geometry cis/trans (or Z/E) isomers.When constitutional isomer can be mutually converted by low energy obstacle, it can occur mutually to make a variation Structure phenomenon (" enantiotropy ").This is disclosed herein containing expressible in such as active constituent of imino group, ketone group or oximido For the form of proton tautomerism phenomenon, or to be referred to as in the compound containing aromatic moiety chemical combination valence tautomerism existing As.This, which follows single compound, can show the isomerism of more than one type.
Be included within the scope of the disclosure be all stereoisomers of active constituent disclosed herein, geometric isomer and Tautomeric form, the compound and one or more mixture of the isomerism including showing more than one type.Also Including be acid-addition salts or alkali salt, wherein ion balance is optically active, for example, d- lactate or l- lysine, or Racemic salt, for example, dl- tartrate or dl- arginine.
Can by routine techniques well known to those skilled in the art separate cis/trans isomers, such as chromatography and point Grade crystallization.
The routine techniques of preparation/separation single enantiomer includes using such as Chiral high pressure liquid chromatogram (HPLC), by suitable Optical voidness precursor chirality synthesis or resolution of racemic object (or salt or derivative of racemate).
Optionally, racemate (or racemic precursor) can with suitable optically active compound such as ethanol synthesis, or In the case of active constituent disclosed herein contains acid or alkaline part, alkali or acid with such as 1- phenyl ethylamine or tartaric acid Reaction.The non-enantiomer mixture of generation can be separated by chromatography and/or fractional crystallization, and ripe by technical staff The one or two of diastereomer are converted to corresponding pure enantiomer by the mode known.
Chipal compounds (and its chiral precursor) of the invention can be used chromatography (usually HPLC) and set in asymmetry It is obtained on rouge in the form that enantiomer is concentrated, wherein mobile phase is made of hydrocarbon, and usually heptane or hexane, contain The isopropanol of 0 to about 50% volume；Typically about 2% to about 20%, the alkylamine of about 0 to about 5% volume；Typically about 0.1% diethylamine.Concentrate eluant provides the mixture of concentration.
Alloisomerism aggregation can be separated by routine techniques well known by persons skilled in the art, see, for example, " spatial chemistry of organic compound " of E.L.Eliel and S.H.Wilen (Wiley, New York, 1994) (Stereochemistry of Organic Compounds), is incorporated herein by reference in their entirety.
The present invention includes the compound of all pharmaceutically acceptable isotope labellings of active constituent disclosed herein, wherein One or more atoms be different from same atoms ordinal number but atomic weight or mass number natural main atom atomic weight or The atom of mass number replaces.
The example for the isotope being suitable for inclusion in the compounds of this invention includes but is not limited to the isotope of hydrogen, 2H and 3H； The isotope of carbon, such as 11C, 13C and 14C；The isotope of chlorine, such as 36Cl；The isotope of fluorine, such as 18F；The isotope of iodine, such as 123I and 125I；The isotope of nitrogen, such as 13N and 15N；The isotope of oxygen, such as 15O, 17O and 18O；The isotope of phosphorus, such as 32P； And the isotope of sulphur, such as 35S.
The active constituent of certain isotope labellings disclosed herein, for example, be incorporated to it is radioisotopic those activity at Point, it is useful in drug and/or substrate tissue distribution research.Radioactive isotope tritium (i.e. 3H) and carbon 14 (i.e. 14C), are examined Consider its be easily incorporated into ready-made detection mode, it is particularly useful to the purpose.
Replaced with higher isotope, such as deuterium (i.e. 2H), it is possible to provide certain treatment advantages, this is because its stronger metabolism is steady It is qualitative, such as increase Half-life in vivo or reduce the dosage needed, thus in some cases may be preferred.
Replaced with the isotope of transmitting positive electron, such as 11C, 18F, 15O and 13N, may be occupied in detection substrate receptor It is useful in positron emission computerized tomography (PET) research.
It usually can be by routine techniques well known by persons skilled in the art or by those of describing class with embodiment As method, replace the unmarked reagent that had previously used to prepare same position disclosed herein using suitable isotope labeling reagent The active constituent of element label.
Think that, by oxygen deficient induction factor 1 and VEGF, free radical and anoxic can increase the destruction to mitochondrial DNA, and It generates and growth of cancers and the relevant undesirable variation of epigenetics that shifts risk.Anoxic is the normal of Locally Advanced solid tumor See feature, the solid tumor is related to therapeutic response reduction, and more the later period is related to malignant progression.Emerging evidence table Bright, influence of the anoxic to malignant progression is changed by the protein group and genome of a series of hypoxia inducibles to be mediated, these variations swash Angiogenesis living, anaerobic metabolism, and tumour cell is enable to survive or escape other processes of its anaerobic environment.Transcription factor Oxygen deficient induction factor 1 (" HIF-1 ") is the instrumentality for making tumour cell adapt to oxygen deprivation stress.With being conducive under anoxic conditions give birth to The tumour cell for protein group and the genome variation deposited can be proliferated, so that anoxic be further aggravated.It is increasingly becoming primary tumor The selection and amplification of new (and the more aggressive) clone of cell type causes and establishes anoxic and the pernicious of malignant progression follows Ring.Anoxic is tended to increase tissue factor table in conjunction with the malignant cell with hematogenous metastasis by increasing tumor cell-platelet It reaches.Anoxic, and though its continue how long, increase the core content of HIF-1 and the mRNA level in-site of erythropoietin(EPO) and VEGF. HIF-1 plays an important role in solid tumor cell grows and survives.The overexpression of HIF-1 α has obtained in many human tumours To proof, and it is poor to the expected response of chemicotherapy.
In consideration of it, hyperbaric oxygen ation (HBOT) can be in certain malignant tumours when thinking to be used together with chemotherapy In have a positive effect, and improve Quality of Life of Patients, inhibit certain oncogenes and tumour growth in vitro, and reduce tumour Bear and limit big tumor cell clone growth.The effect may be by reducing HIF-1, and HIF-1 can change subsequent ginseng With the VEGF gene expression of metastases.VEGF is the initiator of Tumor Angiongesis.Additionally it is believed that vegf expression passes through anoxic Enhance, reinforces VEGF in solid tumor anoxic zone and generate the Tumor Angiongesis for facilitating VEGF driving.
Not think the development for causing the relevant lesion of the free radical of cell death that can stimulate cancer, and cancer can be promoted Growth and transfer.Active oxygen generates Mitochondrial DNA Mutation and raises HIF-I, therefore reduces oxidative damage and be advantageous.
In the presence of the available treatment method for effectively reducing free radical generation and cellular damage.These treatments can be potentially Change epigenetic, and increase the effect of other treatment, such as DCA and 3BP.Therefore, by HBOT and preparation disclosed herein and Method is combined and be may be advantageous.
The invention also includes before or after giving any epigenetic modification agent, using hyperbaric oxygen individually or with it is another The purposes for the treatment of is combined or is given altogether in one epigenetic modification agent.In general, high-pressure oxidation or hyperbaric oxygen ation are such Treatment, wherein individual to be exposed to the scheduled time in the environment for increasing oxygen under the atmosphere pressures for being greater than an atmospheric pressure Section.Hyperbaric oxygen ation has been licensed for treating many illnesss, including embolism, anthracemia, scratch, decompression sickness, poor Blood and infection of bone.Hyperbaric oxygen ation and different high voltage therapy equipment (such as hyperbaric chamber) are generally known in the art, and are retouched It is set forth in different patents, such as the 5th, 865, No. 722 United States Patent (USP), is incorporated herein by reference of text.It is any suitable high Pressure equipment or cabin may be used to the present invention.It can be given before or after hyperbaric oxygentherapy is such as in hyperbaric chamber a kind of or more Kind epigenetic modification agent.It is small that hyperbaric oxygentherapy can occur before or after giving any epigenetic modification agent about 24 When, give before or after any epigenetic modification agent about 5 minutes to about 90 minutes, or give any epigenetic modification agent Before or after about 30 minutes to about 3 hours.
Embodiment
Example 1: it preparation, kit and gives
In various embodiments, the preparation comprising SPB and Quercetin is provided.Said preparation can be combining form.It should Preparation is water-borne using salt, wherein there is about 0.5g to about 1.0g Quercetin and about 5.0g to about 10.0g SPB.In other implementations In scheme, physiological saline medium is replaced using D5 salt water.In other embodiments, preparation also includes antioxidant.
In various embodiments, the preparation comprising LA and Quercetin is provided.Said preparation can be combining form.The system Agent is water-borne using salt, wherein there is about 0.5g to about 1.5g Quercetin and about 200mg to about 1000mgLA.In other embodiment party In case, physiological saline medium is replaced using D5 salt water.
In various embodiments, the preparation comprising LA and SPB is provided.Said preparation can be combining form.Said preparation It is water-borne using salt, wherein the SPB of LA and about 1.0g to about 10.0g in the presence of about 200mg to about 1000mg.In other embodiment party In case, physiological saline medium is replaced using D5 salt water.
In various embodiments, the preparation comprising SPB, Quercetin and glycolytic inhibitor is provided.In different implementations In scheme, glycolytic inhibitor includes at least one of 3-BP, DCA and Octreotide.Said preparation can be combining form.The system Agent is water-borne using salt, wherein there are 0.5g to about 1.5g Quercetin, about 1.0g to about 10.0g SPB.In other embodiments In, physiological saline medium is replaced using D5 salt water.
In various embodiments, the preparation comprising green-tea extract (for example, EGCG) and SPB is provided.Said preparation is Combining form.Said preparation is water-borne using salt, wherein there is about 100mg to about 1.5g green-tea extract and about 1.0g to about 10.0g SPB。
Any preparation of different embodiments can be packaged into kit, as described in this article.Furthermore it is possible to give altogether Give or temporarily densely give active constituent disclosed herein as described above.
Embodiment 2: hyperbaric oxygen ation (HBOT)
After giving or giving any active constituent disclosed herein altogether, HBOT can be given.In various embodiments, exist After giving any active constituent disclosed herein, patient is made to be subjected to HBOT about 5 minutes to about 90 minutes.HBOT environment is included in pressure Under power about 0.5atm to about 2.5atm, and under more preferably about 1.5atm to about 2atm, at least over 95% O2Atmosphere. HBOT occurs about 30 minutes to about 3 hours.
Embodiment 3: research
It is consistent with being disclosed herein, it has carried out following different researchs: by targeted therapies, being used in connection with HDACIs and hyperbaric oxygen Epigenetic modification agent treatment, to reduce the anabolism glycolysis of cancer patient.These treatment displays improve quality of life, And patient survival can be improved.More specifically, comprehensive cancer nursing/method has been carried out to change the place of examination to treat aspiration to such intervention Patient.
Research I: selecting at random and has evaluated 40 patient's records.Inclusion criteria is to be diagnosed as cancer.There is no patient to be arranged Except outside.Patient age is 27 to 83 years old.All patients are diagnosed by their tumour doctor/internist, and are given General surgical procedures treatment, classic chemotherapy or the radiation of standard.In 40 patients, there are 20 to have rejected standard care, Huo Zheyou In conventional selection of the seriousness without being suitble to them of disease.In 40 patients, before changing the place of examination and starting treatment, there are 23 trouble There is the terminal illness of microcosmic or macroscopical many places transfer.In these patients, have 19 (47%) with a variety of chemotherapeutic agents without Effect, and prove that there is disease development by their tumor marker or scanning or recur.
Scheme based on uniqueness exploitation the design of the scheme and is related to using specific natural and synthesize IV come managing patient Therapy using study it is related to clinical test.It is horizontal that IV therapy targets epigenetic, and by antioxidant, Quercetin, DCA, phenylbutyrate sodium and lipoic acid form alone or in combination.All patients receive one or more such treatments.Every time The dosage for the treatment of keeps identical or close to treatment every time, gives Mongolian oak through vein with the dosage of about 0.5g to about 1.5g (50mg/ml) Pi Su.When giving SPB, dosage is about 1.0g to about 10.0g (the 25 to 50ml of 200mg/ml).When giving DCA, dosage is about 500mg to about 6g (maximum 100/kg).When giving lipoic acid, dosage is about 200mg to about 1000mg.Use standard 1.5 to 2.0 Atmospheric pressure implements hyperbaric oxygentherapy, every time using 45-90 minutes (60 minutes average).When giving Octreotide, with about 50mcgs It is subcutaneously given to about 400mcgs.
Start the project after informing that all patients select and agreed to about the possibility of conventional and unconventional treatment.? During therapeutic process, by tumor marker, imaging research and growth of cancers marker, necrosis, LDH and inflammation, CRP, and Natural killer cell activity or lymphocyte count and circulating tumor cell measure the progress of disease.
Following result is obtained during or after completing therapeutic process:
1) subjectivity of QOL increases and (increases energy level, reduces pain scores and improve mood): 100%
2) immune response: increasing natural kill (NK) cell activity or white blood corpuscle (WBC) counts: 35% patient has Initial low NK/WBC, all these patients increase NK activity after the treatment
3) by measurement LDH, the potential reduction of tumor promotion: 40% patient has high LDH, and all these patients are treating All show that LDH is reduced afterwards
4) response of tumor marker, it is sufficient to obtain clinical response: 50%
5) tumor regression in iconography research: 35%
6) CRP reduces (related to survival rate raising): 23%
7) IgF-1 is reduced: 12% in these patients increases IgF-1, shows related to the prognosis in document.It is all these Patient both increases IgF-1 after the treatment
Due to selection cancer patient control group when may have apparent classification Confounding factors, we exist every patient State before intervention is used as control group.Other classification Confounding factors of patient do not change during research.
Study the interpretation of result of I:
1) these data are disclosed compared to control, and patient group response is preferable.In the patient for the treatment of, have 47% when changing the place of examination There is no available conventional selection.In this set, as a result far better compared to the treatment of conventionally form.
2) patient for receiving HBOT and IV therapy simultaneously, with regard to its imaging, quality of life and tumor regression and tumour mark For remembering object control, it is better than the patient for only receiving IV therapy.
3) patient for suffering from 4 phase Terminal Diseases, after receiving above-mentioned project, response has exceeded the nursing expectation of standard, and Receive the patient of chemotherapy and above-mentioned targeted therapies simultaneously, significantly improving with quality of life and chemotherapy response.
In further research, it selects and has evaluated 45 patient's records repeatedly.Inclusion criteria be diagnosed as cancer, and And every course for the treatment of receives minimum treatment in two weeks.There is no patient to be left out.Patient age is 27 to 83 years old.All patients all by Their tumour doctor/internist's diagnosis, and it is given conventional surgical treatment, conventional chemotherapy or the radiation of standard.45 In patient, there are 25 to have rejected standard care, or due to disease seriousness and standard care cannot be responded and not have There is the conventional selection for being suitble to them.
Research II: before changing the place of examination and starting treatment, having 36 (80%) be in for 4 phases in 45 patients, and suffer from it is microcosmic or The terminal illness of many places transfer of macroscopic view.
It is invalid with standard care treatment there are 25 (55%) in these patients, including uses a variety of chemotherapeutics, and lead to Cross they tumor marker or scanning prove disease repeatedly, development or recurrence.
Scheme based on uniqueness exploitation the design of the scheme and is related to being applied in combination specific natural and close come managing patient It is related to clinical test at the available research of IV therapy.It is horizontal that IV therapy targets epigenetic.Also using standard 1.5 to 2.0 atmospheric pressures implement hyperbaric oxygentherapy to some patients, 45-90 minutes each (60 minutes average).
Start the project after informing that all patients select and agreed to about the possibility of conventional and unconventional treatment.? During or after therapeutic process, by tumor marker, imaging research and growth of cancers marker, necrosis, LDH and inflammation, CRP and natural killer cell activity or lymphocyte count and circulating tumor cell measure the progress of disease.
Following result is obtained during or after completing therapeutic process:
1) subjectivity of QOL increases (increase energy level and function, put on weight, improve pain scores): 98% (one Patient has to be infected with the route of antibiotic treatment, and 5 patients have the smaller reaction for needing antihistamine)
2) immune response: increase natural killer cell activity: the initial natural of 19 patient's (42%) measurements kills cell Activity is low, shows that immune function is low.There are 12 to be improved in 19 after the treatment, 1 remains unchanged, and 2 with lower Activity, 3 patients do not follow their treatment post-processing.
3) by measurement LDH, the potential reduction of tumor promotion: measure the LDH of 42 patients (LDH of 3 patients is unknown). 20 patients's (44%) have initial high LDH numerical value, wherein there is 18 (90%) to show LDH reduction after the treatment.
4) response of tumor marker, shows clinical response: 14 patients have normal tumor marker, or not with The relevant tumor marker of their disease.In remaining 31 patient with high tumor marker, there is 27 after therapeutic process Name patient (87%) tumor marker reduce, fluctuated in 2 patients, and in 1 it is constant.
5) in iconography/imaging research, tumor regression: 25 patients, which have, follows the imaging of its situation to report.Other 20 Name is not imaged, or not applicable or uncorrelated.After treatment, there are 19 patients's (76%) to have in 25 patients in its scanning There is active responding.In 7 patients, as a result obscure or constant.Two have development, and 1 occurs after initial reaction.
6) CRP reduces (related to increased survival rate): the CRP of 22 patients is improved.The CRP of 23 patients is in normal Range, or do not check.17 patients increase c reactive protein.16 patients are responded by reducing CRP.1 increase.
7) IgF-1 is reduced: having checked the insulin-like growth factor of 38 patients.10 patients are starting to treat preceding level Increase.After treatment, all these patients' (100%) are shown related to the prognosis in document by reducing horizontal response.? After treatment to normal range (NR), these patients all increase IgF-1.
8) VEGF is reduced: having checked the vascular endothelial growth factor (VEGF) of 20 patients.It was found that 4 patients Increase horizontal related to the high risk of transfer.This 4 patients all reduce VEGF after the treatment.
Due to that may have apparent classification Confounding factors when selecting the control group of cancer patient, we are by every patient State before intervention is used as control group.Other classification Confounding factors of patient do not change during research.
Study the interpretation of result of II:
1) these data are disclosed compared to compareing, and response is preferable in patient group.In the patient for the treatment of, there is 47% changing the place of examination When there is no available conventional selection.In this set, as a result far better compared to the treatment of conventionally form, do not have in these conventional therapies There is available therapeutic choice.
2) patient for receiving HBOT and IV therapy simultaneously, with regard to its imaging, quality of life and tumor regression and tumour mark For remembering object control, it is better than the patient for only receiving IV therapy.
3) patient for suffering from 4 phase terminal illness, after receiving above-mentioned project, response has exceeded the nursing expectation of standard, and And receive the patient of chemotherapy and above-mentioned targeted therapies simultaneously, significantly improving with quality of life and chemotherapy response.
As indicated, the use of epigenetic modification agent improves the cancer survival rate and quality of life of several patients.It was found that Above-described care mode is better than conventional standard care.

Claims (7)

1. it includes two or more epigenetic modification agent for preventing or the pharmaceutical preparation for the treatment of cancer.
2. the pharmaceutical preparation of the unit dose for treating cancer, it includes the epigenetic modifications of combination of two or more form Agent, wherein the epigenetic modification agent is to be enough to cause the dosage of tumor response to exist in human body, the tumor response is being given It is measured after giving about 1 unit dose to about 60 unit doses by laboratory and/or radiologic investigation.
3. the pharmaceutical preparation of the unit dose for treating cancer, it includes the epigenetic modifications of combination of two or more form Agent, wherein the epigenetic modification agent exists to be enough the dosage for causing immune system to enhance, the immune system enhancing is logical Cross human body white blood cell count(WBC) (WBC) and/or natural kill (NK) cell activity after giving about 1 unit dose to about 60 unit doses Increase measure.
4. kit comprising:
The pharmaceutical preparation of unit dose for treating cancer, it includes two or more epigenetic modification agent；
Container, the unit dose are at least partly contained therein.
5. treatment method comprising:
Give mammal one or more epigenetic modification agent；And
The mammal is set to be subjected to high pressure oxygen environment.
6. treatment method comprising:
Give mammal one or more glycolytic inhibitors；And
The mammal is set to be subjected to high pressure oxygen environment.
7. treatment method comprising:
Give mammal one or more glycolytic inhibitors；With
Give mammal one or more epigenetic modification agent.
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